The present invention relates to the use of pharmaceutically active agents known to cause histamine release when intravenously administered to an animal. More particularly the present invention relates to new methods of using such pharmaceutically active agents and new formulations of such agents which address pharmaceutically-induced histamine release.
The cardiovascular and respiratory effects indicative of undesirable degrees of histamine release which are specific to some conventional pharmacological agents have been troubling clinicians for decades. The clinical observations associated with an undesirable degree of histamine release are typified by cutaneous flushing about the face, neck and/or chest, sometimes accompanied by hypotension and/or tachycardia and/or nausea and vomiting. In some cases, the physical manifestations of an undesirably high degree of histamine release can include very serious and potentially fatal reactions such as bronchospasm, wheezing, and anaphylactoid reactions and anaphylactic shock. An explanation of the reason(s) that these pharmacological agents cause histamine release in vivo has eluded scientists for years.
Conventional pharmacological agents which are known to cause or suspected to be capable of causing histamine release include intravenously administered hypnotics, analgesics, sedatives, optiates, anesthetics, neuromuscular blocking agents (i.e., “neuromuscular blockers”), contrast agents employed in imaging (i.e., radiographic contrast media, radio imaging agents and other contrast agents, hereinafter collectively “imaging agents”), hormones for diagnostic procedures, and certain antibiotics, NSAIDs, anticoagulants, ACE inhibitors and benzodiazepine receptor antagonists. These agents may be administered intravenously as a bolus or rapid infusion, which can, in addition to their desired therapeutic, diagnostic or medicinal effect, cause the release of histamine. Histamine release is often the most prevalent adverse reaction of certain of these pharmacological agents.
Histamine release could occur through both immunologic and non-immunologic mechanisms. The more immediate or rapid reactions elicited by these pharmacological agents are believed to occur via release of histamine via a non-immunologic mechanism. The latter are often referred to as anaphylactoid reactions.
The precise mechanism by which these drugs cause the release of histamine is not clear. Mast cells and basophils are possible sources of the released histamine, but other in vivo sources may also exist. Mechanistic studies, especially studies conducted in vitro with mast cells are complicated by the tremendous heterogeneity that exists not only between species, but within a single individual. Given the number of different sources of histamine, it is possible that different mechanisms in different cells and tissue may be involved at any one time.
Clinically, it is known that slowing the rate of injection of these agents from 5 seconds to 30 seconds decreases the incidence of cardiovascular effects typical of histamine release. Slowing the rate of administration is currently the preferred method of avoiding the risks associated with substantial histamine release. However, slowing the rate of administration is not an acceptable course of action in some clinical situations. For example, slowing the rate of administration is unacceptable in emergency medical situations, especially when anesthesia and intubation prior to emergency surgical procedures must occur rapidly. Furthermore, it is known that slowing administration of certain pharmacological agents can disproportionately decrease the speed of onset of activity and/or the potency of the drug.
There remains a need in the art for methods of addressing the histamine release side effect associated with these pharmacological agents.